BACKGROUND OF THE INVENTION
[0001] Thrombin is an important serine protease in hemostasis and thrombosis. One of the
key actions of thrombin is receptor activation. A functional human thrombin receptor
(TR), cloned by Coughlin in 1991 (
T.-K. Vu, Cell 1991, 64, 1057), was found to be a member of the G-protein coupled receptor (GPCR) superfamily.
The receptor activation putatively occurs by N-terminal recognition and proteolytic
cleavage at the Arg-41/Ser-42 peptide bond to reveal a truncated N-terminus. This
new receptor sequence, which has an SFLLRN (Ser-Phe-Leu-Leu-Arg-Asn) N-terminus acting
as a tethered ligand to recognize a site on the receptor, can trigger activation and
signal transduction leading to platelet aggregation. Peptide analogues based on this
hexapeptide have also shown good agonist activity leading to platelet aggregation.
Since 1991, two other prctease-activated receptors with extensive homology to the
thrombin receptor, "PAR-2" and "PAR-3," were cloned, and found to be activated by
similar N-terminal hexapeptide sequences. Hence, agonists / antagonists of the thrombin
receptor, such as those included in this invention, may be useful in activating /
antagonizing these protease-activated receptors as well.
[0002] Activation of the thrombin receptor by agonist compounds of this invention may mimic
thrombins role in tissue repair. Thrombin can initiate effects related to wound healing,
such as: increasing vascular permeability to allow entry of cells and fluid into injured
tissue (
A. B. Malik, Semin. Thromb. Haemostasis 1986, 184); increasing the synthesis of PDGF by endothelial cells (
J. M. Harlan, J. Cell Biol. 1986, 103, 1129); and increasing the adhesion of platelets, monocytes, and neutrophils to endothelial
cells (
M. P. Bevilacqua, Science 1989, 243, 1160). Tissue repair in rats following surgical incision is accelerated by the use of
thrombin (
D. H. Carney, J. Clin. Invest. 1992, 89, 1469). Thus, agonists at the thrombin receptor may be useful as wound healing agents or
in tissue repair.
[0003] The peptide-based antagonists of the thrombin receptor in this present invention
may show efficacy against myocardial infarction, stroke, restenosis, angina, atherosclerosis,
and ischemic attacks by virtue of their ability to prevent platelet aggregation. The
thrombin receptor has also been identified on other cell types: endothelial, fibroblast,
osteosarcoma, smooth muscle, and neuronal/glia. Thrombin activation of endothelial
cells upregulates P-selectin to induce polymorphonuclear leukocyte adhesion - an inflammatory
response of the vessel wall (
Y. Sugama, J. Cell Biol. 1992, 119, 935). In fibroblasts, thrombin receptor activation induces proliferation and transmission
of mitogenic signals (
D. T. Hung, J. Cell Biol. 1992, 116, 827). Thrombin has been implicated in osteoblast proliferation through its activation
of osteoblast cells (
D. N. Tatakis, Biochem. Biophys. Res. Commun. 1991, 174, 181). Thrombin has been implicated in the regulation and retraction of neurons (
K. Jalink, J. Cell. Biol. 1992, 118, 411). Therefore, in this context, the antagonist compounds of this invention may also
be useful against inflammation, restenosis, cancer, osteoporosis, and neurodegenerative
disorders.
SUMMARY OF THE INVENTION
[0004] The present invention is directed to compounds represented by the following general
formula (I):

wherein A
1, A
2, A
3, X, Y, and Z are defined later.
[0005] These compounds are thrombin receptor modulators and may be useful either as agonists
in wound healing and tissue repair or as antagonists in myocardial infarction, stroke,
restenosis, angina, atherosclerosis, ischemic attacks, inflammation, cancer, osteoporosis,
or neurodegenerative disorders.
DETAILED DESCRIPTION OF THE INVENTION
[0006] More particularly, the present invention is directed to compounds of the following
formula (I):

wherein
A1 is an alkyl amino acid residue selected from Cha, Leu and Ile, an amino alkyl amino
acid residue selected from Arg and Lys, or an aryl amino acid residue selected from
Phe, substituted Phe, Tyr, or Trp;
A2 is an amino alkyl amino acid residue selected from Lys, Orn, Arg, and homo Arg;
A3 is an aryl amino acid residue selected from Phe, substituted Phe, Tyr, Trp, phenyl-Gly,
2-thienyl-Ala and 3-thienyl-Ala, an alkyl amino acid residue selected from Cha, Leu
and Ile, an amido alkyl amino acid selected from Asn and Gln, or an amino alkyl amino
acid residue selected from Arg, homo Arg, Orn and Lys;
X is selected from CO, CS, or SO2;
Y is selected from aryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl,
heteroaryl, substituted heteroaryl, heteroarylethylenyl, substituted heteroarylethylenyl,
arylacrylamidoheteroaryl, substituted arylacrylamidoheteroaryl, heteroarylacrylamidoheteroaryl
and substituted heteroarylacrylamidoheteroaryl, preferably, Y is not pyrrolidinyl,
substituted pyrrolidinyl, phenyl or 2-aminophenyl; most preferably, Y is selected
from heteroaryl, substituted heteroaryl, arylacrylamidoheteroaryl, and substituted
arylacrylamidoheteroaryl;
Z is selected from NH2, NH-alkyl, NH-aralkyl, or an amino alkyl amino acid residue selected from Arg-NH2; and
wherein all amino acids are of the L configuration; and the pharmaceutically acceptable
salts thereof.
[0007] In the compounds of formula (I), the amino acid residues comprising the A
1, A
2, and A
3 substituents are attached to the adjacent moiety according to standard nomenclature
so that the amino-terminus (N-terminus) of the amino acid is drawn on the left and
the carboxy-terminus of the amino acid is drawn on the right. So, for example, in
Compound 1, where A
1 is Cha, A
2 is Arg and A
3 is Phe, the N-terminus of the Cha (A
1) is attached to the X substituent and the carboxy-terminus of the Cha (A
1) is attached to the N-terminus of the A
2 substituent (Arg), similarly, the the N-terminus of the Arg (A
2) is attached to the carboxy-terminus of the A
1 substituent and the carboxy-terminus of the Arg (A
2) is attached to the N-terminus of the A
3 substituent (Phe), similarly, the N-terminus of the Phe (A
3) is attached to the carboxy-terminus of the A
2 substituent and the carboxy-terminus of the Phe (A
3) is attached to the Z substituent.
[0008] When a particular group is "substituted" (e.g., Phe, heterocycloalkyl, heteroaryl,
acrylamidoheteroaryl), that group may have from 1 to 4 substituents independently
selected from: halo (I, Br, Cl, F), C
1-C
8 alkyl, C
1-C
8 alkoxy, amino, amido, carboxyl, cyano, nitro, fluorinated C
1-C
8 alkyl, fluorinated C
1-C
8 alkoxy, or aryl (preferably, phenyl or substituted phenyl).
[0009] The term "subject" as used herein, refers to an animal, preferably a mammal, most
preferably a human, who has been the object of treatment, observation or experiment.
[0010] The term "therapeutically effective amount" as used herein, means that amount of
active compound or pharmaceutical agent that elicits the biological or medicinal response
in a tissue system, animal or human that is being sought by a researcher, veterinarian,
medical doctor or other clinician, which includes alleviation of the symptoms of the
disease or disorder being treated.
[0011] As used herein, unless otherwise noted alkyl and alkoxy whether used alone or as
part of a substituent group, include straight and branched chains having 1 to 8 carbon
atoms, or any number within this range. For example, alkyl radicals include methyl,
ethyl, propyl, isopropyl,
n-butyl, isobutyl,
sec-butyl,
t-butyl,
n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl,
n-hexyl, 2-hexyl and 2-methylpentyl. Alkoxy radicals are oxygen ethers formed from
the previously described straight or branched chain alkyl groups. Cycloalkyl groups
contain 3 to 8 ring carbons and preferably 5 to 7 carbons. Similarly, alkenyl and
alkynyl groups include straight and branched chain alkenes and alkynes having 1 to
8 carbon atoms, or any number within this range.
[0012] The term "aryl" as used herein, alone or in combination with other terms, represents
an aromatic hydrocarbon group. Examples of aryl groups include, but are not limited
to, phenyl, naphthyl, phenanthryl, anthryl, biphenylenyl, fluorenyl, or azulenyl.
Preferred aryl groups include phenyl, naphthyl and biphenylenyl.
[0013] The term "heterocycloalkyl" as used herein represents an unsubstituted or substituted
stable three to seven membered monocyclic saturated ring system which consists of
carbon atoms and from one to three heteroatoms selected from N, O or S, and wherein
the nitrogen or sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom
may optionally be quaternized. The heterocyloalkyl group may be attached at any heteroatom
or carbon atom which results in the creation of a stable structure. Examples of such
heterocyloalkyl groups include, but are not limited to azetidinyl, piperidinyl, piperazinyl,
oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl,
tetrahydroimidazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl,
thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl.
[0014] The term "heteroaryl" as used herein represents an unsubstituted or substituted stable
five or six membered monocyclic aromatic ring system or an unsubstituted or substituted
nine or ten membered benzo-fused heteroaromatic ring system which consists of carbon
atoms and from one to three heteroatoms selected from N, O or S, and wherein the nitrogen
or sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may
optionally be quaternized. The heteroaryl group may be attached at any heteroatom
or carbon atom which results in the creation of a stable structure. Examples of heteroaryl
groups include, but are not limited to pyridyl, pyridazinyl, thienyl, furanyl, imidazolyl,
isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, benzimidazolyl,
benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, indolyl,
benzothiazolyl, benzothiadiazolyl, benzotriazolyl or quinolinyl. Prefered heteroaryl
groups include pyridyl, pyrrolyl, pyrazinyl, thiadiazolyl, pyrazolyl, thienyl, triazolyl
and quinolinyl.
[0015] The term "aralkyl" means an alkyl group substituted with an aryl group (e.g., benzyl,
phenylethyl). Similarly, the term "aralkoxy" indicates an alkoxy group substituted
with an aryl group (e.g., benzyloxy).
[0016] The term "acyl" as used herein means an organic radical having 1 to 6 carbon atoms
(branched or straight chain) derived from an organic acid by removal of the hydroxyl
group.
[0017] The term "amido" refers to the group C(O)NH or C(O)NH
2.
[0018] The term "carbonyl" refers to the group C(O).
[0019] The term "arylacrylamidoheteroaryl" as used herein means an aryl group attached to
an ethylene which is attached to an amido group which is attached to a heteroaryl
group, where the terms "aryl", "amido" and "heteroaryl" are as defined above. The
term "arylacrylamidoheteroaryl" can therefore refer to a group such as Aryl-C=C-C(O)-NH-heteroaryl,
with a specific example of such an "arylacrylamidoheteroaryl" group being 5-( -Me-cinnamamido)triazol-3-yl
O having the structure

[0020] It is intended that the definition of any substituent or variable at a particular
location in a molecule be independent of its definitions elsewhere in that molecule.
It is understood that substituents and substitution patterns on the compounds of this
invention can be selected by one of ordinary skill in the art to provide compounds
that are chemically stable and that can be readily synthesized by techniques know
in the art as well as those methods set forth herein.
[0021] As used herein, the term "composition" is intended to encompass a product comprising
the specified ingredients in the specified amounts, as well as any product which results,
directly or indirectly, from combinations of the specified ingredients in the specified
amounts.
[0022] The compounds of the present invention may also be present in the form of a pharmaceutically
acceptable salt. The pharmaceutically acceptable salt generally takes a form in which
the nitrogen of the amino-substituted heterocycle or an amino-acid's basic side-chain
is protonated with an inorganic or organic acid. Representative organic or inorganic
acids include hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric,
phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic,
tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benezenesulfonic,
oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic,
saccharinic or trifluoroacetic.
[0023] The present invention includes within its scope prodrugs of the compounds of this
invention. In general, such prodrugs will be functional derivatives of the compounds
which are readily convertible
in vivo into the required compound. Thus, in the methods of treatment of the present invention,
the term "administering" shall encompass the treatment of the various disorders described
with the compound specifically disclosed or with a compound which may not be specifically
disclosed, but which converts to the specified compound
in vivo after administration to the patient. Conventional procedures for the selection and
preparation of suitable prodrug derivatives are described, for example, in "
Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
[0024] Where the compounds according to this invention have at least one chiral center,
they may accordingly exist as enantiomers. Where the compounds possess two or more
chiral centers, they may additionally exist as diastereomers. It is to be understood
that all such isomers and mixtures thereof are encompassed within the scope of the
present invention. Furthermore, some of the crystalline forms for the compounds may
exist as polymorphs and as such are intended to be included in the present invention.
In addition, some of the compounds may form solvates with water (i.e., hydrates) or
common organic solvents, and such solvates are also intended to be encompassed within
the scope of this invention.
[0025] Until the present invention by Applicants, the known thrombin receptor agonists were
peptides (i.e., PAR-1 peptide agonists) having a minimum sequence length of five amino
acids. Applicants have unexpectantly discovered the instant thrombin receptor agonists
which are significantly truncated or that contain a heterocycle within the peptide
backbone as a peptidomimetic unit.
[0026] Particularly preferred compounds of the present invention that could be useful as
thrombin receptor agonists include those compounds shown in Table 1, which shows EC
50 values for platelet aggregation and binding IC
50 at the thrombin receptor. Amino acids bear the "L" absolute configuration unless
denoted otherwise.

[0027] Particularly preferred compounds of the present invention that could be useful as
thrombin receptor antagonists or mixed agonists / antagonists include those compounds
shown in Table 2, which shows IC
50 values for inhibition of platelet aggregation (gel-filtered platelets aggregation
induced by thrombin) and binding IC
50 at the thrombin receptor. Amino acids bear the "L" absolute configuration unless
denoted otherwise.

[0028] Particularly preferred compounds of the present invention are:
(5-Bromopyridin-3-yl)carbonyl-cyclohexylalanyl-arginyl-phenylalanineamide;
2-Chromonylcarbonyl-cyclohexylalanyl-arginyl-phenylalanineamide;
(5-Aminotriazol-3-yl)carbonyl-cyclohexylalanyl-arginyl-phenylalanineamide;
[5-(-Methyl)cinnamamidotriazol-3-yl]carbonyl-cyclohexylalanyl-arginyl-phenylalanineamide;
{5-[3-(1-Naphthyl)acrylamido]triazol-3-yl}carbonyl-cyclohexylalanyl-arginyl-phenylalanineamide;
[Quinoxalin-2-yl]carbonyl-cyclohexylalanyl-arginyl-phenylalanineamide;
[5-(o-Chlorocinnamamido)triazol-3-yl]carbonyl-cyclohexylalanyl-arginyl-phenylalanineamide;
(6-Aminopyridin-3-yl)carbonyl-cyclohexylalanyl-arginyl-phenylalanineamide;
(5-Aminotriazol-3-yl)carbonyl-phenylalanyl-arginyl-phenylalanyl-arginineamide;
(5-Aminotriazol-3-yl)carbonyl-cyclohexylalanyl-lysinyl-phenylalanineamide;
{5-[3-(2-Thienyl)acrylamido]triazol-3-yl}carbonyl-cyclohexylalanyl-arginyl-phenylalanineamide;
[5-cinnamamidotriazol-3-yl]carbonyl-cyclohexylalanyl-arginyl-phenylalanineamide;
(6-Cinnamamidopyridin-3-yl)carbonyl-cyclohexylalanyl-arginyl-phenylalanineamide; or
(5-Chloro-3-methyl-benzothiophen-2-yl) carbonyl-cyclohexylalanyl-arginyl-phenylalanineamide;
and pharmaceutically acceptable salts thereof.
[0029] The modulators of this invention may be prepared using solid phase chemistry as shown
in Scheme A.

[0030] Thus, the resin is Fmoc deprotected via agitation using piperidine or any dialkyl
amine in an appropriate solvent such as DMF, washed with fresh solvent and then coupled
with an Fmoc protected amino-acid A
3 using suitable coupling reagents such as diisopropylcarbodiimide (DIC) or dicyclohexylcarbodiimide
(DCC) or Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl) along with hydroxybenzotriazole
(HOBT) in DMF or another dipolar aprotic solvent. After washing, the amino-acid loaded
resin is Fmoc deprotected as above with a dialkyl amine in DMF and coupled again with
the second Fmoc protected amino-acid A
2 with a coupling agent as above. This Fmoc dipeptido loaded resin is further deprotected
with dialkylamine in DMF, or appropriate solvent, and coupled again to the Fmoc amino-acid
A
1 using a coupling agent as above. The tripeptido resin is deprotected with a dialkyl
amine in DMF and coupled to the substituted acid Y-X-OH with an appropriate coupling
agent. At this point the product may be cleaved from the resin using a strong acid
such as trifluoroacetic (TFA) acid in any inert solvent, such as DCM, to give the
peptide amide 1. However, if the Y group possesses a protected amino functionality,
such as Fmoc-amino, this may be deprotected and the amino-peptide product cleaved
from the resin or the freed-up amine can be reacted further prior to cleavage of the
peptide from the resin. Thus, the Fmoc can be removed using a dialkyl amine in DMF
as above and the amino-peptide can be 1) cleaved from the resin with TFA or 2) coupled
with an aryl acrylic acid, using appropriate coupling agent such as BOP-Cl, and the
product can be cleaved from the resin with TFA to afford peptide 11. Following this
general route, preparation of compound 1 as outlined in Scheme 1 is prepared, as described
in more detail in the experimental section.

[0031] Alternatively, the compounds may be prepared via normal solution phase chemistry
as shown in Scheme B.

[0032] Thus, Fmoc protected amino-acid A
3 can be coupled with an amine ZH using the normal peptide coupling agents such as
DIC or DCC and HOBT in dipolar aprotic solvents such as acetonitrile (ACN) or dimethyl
formamide (DMF). The isolated product can then be Fmoc deprotected with diethylamine
(DEA), or another dialkyl amine, in a dipolar aprotic solvent such as ACN, and the
resultant amine coupled to the second Fmoc protected amino-acid A
2. This dipeptide can similarly be deprotected as above and coupled with an appropriate
coupling agent with Fmoc protected amino-acid A
1 to give the Fmoc-tripeptide. Deprotection of the Fmoc group with a dialkyl amine
is followed by coupling of this tripeptide to the acid Y-X-OH using a coupling agent
such as DIC with HOBT to give the product
111. Using this general route, synthesis of compound 2 was prepared as outlined in Scheme
2, and further described in the experimental section.

[0033] The utility of the compounds of formula (I) to act as thrombin receptor modulators
can be determined according to the procedures described in Examples 4 to 5 herein.
The present invention therefore provides a method of treating a condition mediated
by modulation of the thrombin receptor in a subject in need thereof which comprises
administering any of the compounds or pharmaceutical compositions as defined herein
in a quantity effective to treat the condition. Additionally, the present invention
includes the use of a compound of formula (I) for the preparation of a medicament
for the treatment of a condition mediated by modulation of the thrombin receptor.
The compound may be administered to a patient by any conventional route of administration,
including, but not limited to, intravenous, oral, subcutaneous, intramuscular, intradermal
and parenteral.
[0034] The present invention also provides pharmaceutical compositions comprising one or
more compounds of this invention in association with a pharmaceutically acceptable
carrier.
[0035] To prepare the pharmaceutical compositions of this invention, one or more compounds
of formula (I) or salt thereof of the invention as the active ingredient, is intimately
admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding
techniques, which carrier may take a wide variety of forms depending of the form of
preparation desired for administration, e.g., oral or parenteral such as intramuscular.
In preparing the compositions in oral dosage form, any of the usual pharmaceutical
media may be employed. Thus, for liquid oral preparations, such as for example, suspensions,
elixirs and solutions, suitable carriers and additives include water, glycols, oils,
alcohols, flavoring agents, preservatives, coloring agents and the like; for solid
oral preparations such as, for example, powders, capsules, caplets, gelcaps and tablets,
suitable carriers and additives include starches, sugars, diluents, granulating agents,
lubricants, binders, disintegrating agents and the like. Because of their ease in
administration, tablets and capsules represent the most advantageous oral dosage unit
form, in which case solid pharmaceutical carriers are obviously employed. If desired,
tablets may be sugar coated or enteric coated by standard techniques. For parenterals,
the carrier will usually comprise sterile water, through other ingredients, for example,
for purposes such as aiding solubility or for preservation, may be included. Injectable
suspensions may also be prepared, in which case appropriate liquid carriers, suspending
agents and the like may be employed. The pharmaceutical compositions herein will contain,
per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like,
an amount of the active ingredient necessary to deliver an effective dose as described
above. The pharmaceutical compositions herein will contain, per unit dosage unit,
e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of
from about 0.03 mg to 100 mg/kg (preferred 0.1-30 mg/kg) and may be given at a dosage
of from about 0.1-300 mg/kg/day (preferred 1-50 mg/kg/day). The dosages, however,
may be varied depending upon the requirement of the patients, the severity of the
condition being treated and the compound being employed. The use of either daily administration
or post-periodic dosing may be employed.
[0036] Preferably these compositions are in unit dosage forms from such as tablets, pills,
capsules, powders, granules, sterile parenteral solutions or suspensions, metered
aercsol or liquid sprays, drops, ampoules, autoinjector devices or suppositories;
for oral parenteral, intranasal, sublingual or rectal administration, or for administration
by inhalation or insufflation. Alternatively, the composition may be presented in
a form suitable for once-weekly or once-monthly administration; for example, an insoluble
salt of the active compound, such as the decanoate salt, may be adapted to provide
a depot preparation for intramuscular injection. For preparing solid compositions
such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier,
e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol,
talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical
diluents, e.g. water, to form a solid preformulation composition containing a homogeneous
mixture of a compound of the present invention, or a pharmaceutically acceptable salt
thereof. When referring to these preformulation compositions as homogeneous, it is
meant that the active ingredient is dispersed evenly throughout the composition so
that the composition may be readily subdivided into equally effective dosage forms
such as tablets, pills and capsules. This solid preformulation composition is then
subdivided into unit dosage forms of the type described above containing from 0.1
to about 500 mg of the active ingredient of the present invention. The tablets or
pills of the novel composition can be coated or otherwise compounded to provide a
dosage form affording the advantage of prolonged action. For example, the tablet or
pill can comprise an inner dosage and an outer dosage component, the latter being
in the form of an envelope over the former. The two components can be seperated by
an enteric layer which serves to resist disintegration in the stomach and permits
the inner component to pass intact into the duodenum or to be delayed in release.
A variety of material can be used for such enteric layers or coatings, such materials
including a number of polymeric acids with such materials as shellac, cetyl alcohol
and cellulose acetate.
[0037] The liquid forms in which the novel compositions of the present invention may be
incorporated for administration orally or by injection include, aqueous solutions,
suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with
edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well
as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending
agents for aqueous suspensions, include synthetic and natural gums such as tragacanth,
acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone
or gelatin.
[0038] Where the processes for the preparation of the compounds according to the invention
give rise to mixture of stereoisomers, these isomers may be separated by conventional
techniques such as preparative chromatography. The compounds may be prepared in racemic
form, or individual enantiomers may be prepared either by enantiospecific synthesis
or by resolution. The compounds may, for example, be resolved into their components
enantiomers by standard techniques, such as the formation of diastereomeric pairs
by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric
acid and/or (+)-di-p-toluoyl-1-tartaric acid followed by fractional crystallization
and regeneration of the free base. The compounds may also be resolved by formation
of diastereomeric esters or amides, followed by chromatographic separation and removal
of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral
HPLC column.
[0040] The method of treating conditions modulated by the thrombin receptor described in
the present invention may also be carried out using a pharmaceutical composition comprising
any of the compounds as defined herein and a pharmaceutically acceptable carrier.
The pharmaceutical composition may contain between about 0.01 mg and 100 mg, preferably
about 5 to 50 mg, of the compound, and may be constituted into any form suitable for
the mode of administration selected. Carriers include necessary and inert pharmaceutical
excipients, including, but not limited to, binders, suspending agents, lubricants,
flavorants, sweeteners, preservatives, dyes, and coatings. Compositions suitable for
oral administration include solid forms, such as pills, tablets, caplets, capsules
(each including immediate release, timed release and sustained release formulations),
granules, and powders, and liquid forms, such as solutions, syrups, elixers, emulsions,
and suspensions. Forms useful for parenteral administration include sterile solutions,
emulsions and suspensions.
[0041] Advantageously, compounds of the present invention may be administered in a single
daily dose, or the total daily dosage may be administered in divided doses of two,
three or four times daily. Furthermore, compounds for the present invention can be
administered in intranasal form via topical use of suitable intranasal vehicles, or
via transdermal skin patches well known to those of ordinary skill in that art. To
be administered in the form of a transdermal delivery system, the dosage administration
will, of course, be continuous rather than intermittent throughout the dosage regimen.
[0042] For instance, for oral administration in the form of a tablet or capsule, the active
drug component can be combined with an oral, non-toxic pharmaceutically acceptable
inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired
or necessary, suitable binders; lubricants, disintegrating agents and coloring agents
can also be incorporated into the mixture. Suitable binders include, without limitation,
starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners,
natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate,
magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite,
xanthan gum and the like.
[0043] The liquid forms in suitably flavored suspending or dispersing agents such as the
synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and
the like. For parenteral administration, sterile suspensions and solutions are desired.
Isotonic preparations which generaly contain suitable preservatives are employed when
intravenous administration is desired.
[0044] The compound of the present invention can also be administered in the form of liposome
delivery systems, such as small unilamellar vesicles, large unilamellar vesicles,
and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids,
such as cholesterol, stearylamine or phophatidylcholines.
[0045] Compounds of the present invention may also be delivered by the use of monoclonal
antibodies as individual carriers to which the compound molecules are coupled. The
compounds of the present invention may also be coupled with soluble polymers as targetable
drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol,
polyhydroxy-ethylaspartamidephenol, or polyethyl eneoxidepolylysine substituted with
palmitoyl residue. Furthermore, the compounds of the present invention may be coupled
to a class of biodegradable polymers useful in achieving controlled release of a drug,
for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid,
polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked
or amphipathic block copolymers of hydrogels.
[0046] Compounds of this invention may be administered in any of the foregoing compositions
and according to dosage regimens established in the art whenever treatment of thrombotic
disorders is required.
[0047] The daily dosage of the products may be varied over a wide range from 0.01 to 1,000
mg per adult human per day. For oral administration, the compositions are preferably
provided in the form of tablets containing, 0.01,0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0,
15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for
the symptomatic adjustment of the dosage to the patient to be treated. An effective
amount of the drug is ordinarily supplied at a dosage level of from about 0.1 mg/kg
to about 300 mg/kg of body weight per day. Preferably, the range is from about 1 to
about 50 mg/kg of body weight per day. The compounds may be administered on a regimen
of 1 to 4 times per day.
[0048] Optimal dosages to be administered may be readily determined by those skilled in
the art, and will vary with the particular compound used, the mode of administration,
the strength of the preparation, the mode of administration, and the advancement of
the disease condition. In addition, factors associated with the particular patient
being treated, including patient age, weight, diet and time of administration, will
result in the need to adjust dosages.
[0049] To prepare the pharmaceutical compositions of this invention, one or more compounds
of formula (I) or salt thereof of the invention as the active ingredient, is intimately
admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding
techniques, which carrier may take a wide variety of forms depending of the form of
preparation desired for administration, e.g., oral or parenteral such as intramuscular.
In preparing the compositions in oral dosage form, any of the usual pharmaceutical
media may be employed. Thus, for liquid oral preparations, such as for example, suspensions,
elixirs and solutions, suitable carriers and additives include water, glycols, oils,
alcohols, flavoring agents, preservatives, coloring agents and the like; for solid
oral preparations such as, for example, powders, capsules, caplets, gelcaps and tablets,
suitable carriers and additives include starches, sugars, diluents, granulating agents,
lubricants, binders, disintegrating agents and the like. Because of their ease in
administration, tablets and capsules represent the most advantageous oral dosage unit
form, in which case solid pharmaceutical carriers are obviously employed. If desired,
tablets may be sugar coated or enteric coated by standard techniques. For parenterals,
the carrier will usually comprise sterile water, through other ingredients, for example,
for purposes such as aiding solubility or for preservation, may be included. Injectable
suspensions may also be prepared, in which case appropriate liquid carriers, suspending
agents and the like may be employed. The pharmaceutical compositions herein will contain,
per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like,
an amount of the active ingredient necessary to deliver an effective dose as described
above. The pharmaceutical compositions herein will contain, per unit dosage unit,
e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of
from about 0.03 mg to 100 mg/kg (preferred 0.1-30 mg/kg) and may be given at a dosage
of from about 0.1-300 mg/kg/day (preferred 1-50 mg/kg/day). The dosages, however,
may be varied depending upon the requirement of the patients, the severity of the
condition being treated and the compound being employed. The use of either daily administration
or post-periodic dosing may be employed.
[0050] The following Examples are set forth to aid in the understanding of the invention,
and are not intended and should not be construed to limit in any way the invention
set forth in the claims which follow thereafter.
[0051] Protected amino acids were purchased from Novabiochem, Synthetech or Bachem Bioscience
Inc. All other chemicals were purchased from Aldrich Chemical Company, Inc. High field
1H NMR spectra were recorded on a Bruker AC-300 spectrometer at 300 MHz, and coupling
constants are given in Herz. Microanalyses were performed at Robertson Microlit Laboratories,
Inc., Madison, New Jersey. In the examples and throughout this application, the following
abbreviations have the meanings recited hereinafter:
- ACN
- Acetonitrile
- BOP-Cl
- Bis(2-oxo-3-oxazolidinyl)phosphinic chloride
- DCM
- Dichloromethane
- DCC
- Dicyclohexylcarbodiimide
- DIC
- Diisopropylcarbodiimide
- DEA
- Diethylamine
- DMAP
- 4-Dimethylaminopyridine
- DMF
- N, N-Dimethylformamide
- Et2O
- Diethyl ether
- Fmoc
- Fluorenylmethoxycarbonyl
- HOBT
- Hydroxybenzotriazole
- Me
- Methyl
- Ph
- Phenyl
- Pmc
- 2,2,5,7,8-Pentamethylchroman-6-sulfonyl
- RT
- room temperature
- TFA
- Trifluoroacetic acid
[0052] Amino acid abbreviations are defined below:
- Arg
- Arginine
- Asn
- Asparagine
- Cha
- Cyclohexylalanine
- Gln
- Glutamine
- hArg
- Homoarginine
- hPhe
- Homophenylalanine
- Ile
- Isoleucine
- Leu
- Leucine
- Lys
- Lysine
- Orn
- Ornithine
- Phe
- Phenylalanine
- Phgly
- Phenylglycine
- 2-Thala
- 2-Thienylalanine
- 3-Thala
- 3-Thienylalanine
- Trp
- Tryptophan
- Tyr
- Tyrosine
EXAMPLE 1
N-(5-Amino-1,2,4-triazol-3-yl)carbonyl)-cyclohexylalanyl-argininyl-phenylalanine amide
(1)
[0053]

Rink amide resin (4.0 g, 3.24 mm) was placed in a solid phase hour-glass reactor and
agitated (nitrogen bubbling) with 20% piperidine / DMF (25 mL) for 1 hr. The solution
was drained off and the resin was washed with DMF (4X), DCM (3X), and DMF (3X). The
resin was combined with Fmoc-Phe-OH (3.77 g, 9.75 mm), HOBT (1.5 g, 9.75 mm) and DIC
(1.23 g, 9.75 mm) in DMF (25 mL) and agitated in the reactor for 16 hr at ambient
temperature. The solution was drained and resin was washed with DMF (5X) and DCM (4X)
and dried
in vacuo. A portion (1.0 g, 0.80 mm) was agitated in the reactor at ambient temperature with
20% piperidne / DMF (15 mL) for 1 hr, the solution was drained and resin washed with
DMF (4X), DCM (3X), and DMF (3X). This was combined with Fmoc-Arg(Pmc)-OH (1.84 g,
2.4 mm), HOBT (0.37 g, 2.4 mm), and DIC (0.31 g, 2.4 mm) in DMF (10 mL) and agitated
at ambient temperature for 16 hr. After draining the solution, the resin was washed
with DMF (4X), and ECM (3X). Half of this batch was washed with DMF (3X) and then
agitated with 20% piperidine / DMF (10 mL) for 1 hr. The solution was drained and
the resin was washed with DMF (4X), DCM (3X), and DMF (3X) and then combined with
Fmoc-Cha-OH (0.47 g, 1.2 mm), HOBT (0.18 g, 1.2 mm) and DIC (0.15 g, 1.2 mm) in DMF
(10 mL) and agitated for 16 hr at ambient temperature. The solution was drained and
the resin was washed with DMF (4X), DCM (3X), and DMF (3X) and treated with 20% piperidine
/ DMF for 1 hr. The solution was drained and the resin was washed with DMF (4X) and
then combined with Fmoc-3-amino-1,2,4 triazole-5-carboxylic acid (0.42 g, 1.2 mm),
HOBT (0.18 g, 1.2 mm), and DIC (0.15 g, 1.2 mm) in DMF (10 mL) and agitated at ambient
temperature for 16 hr. The solution was drained off, and the resin was washed with
DMF (4X), DCM (3X), and DMF (3X) and then agitated with 20% piperidine / DMF (15 mL)
for 1 hr. The solution was drained and the resin was washed with DMF (4X), and DCM
(3X) and dried under a nitrogen stream. The resin was then agitated with 99% TFA (20
mL) at ambient temperature for 1.5 hr. The TFA solution was collected and evaporated
in vacuo to an oil, which was triturated with Et
2O (3X) to give a white solid (152 mg). Purification was accomplished via reverse phase
HPLC using 0.16% TFA in ACN / 0.20% TFA in water (35:65) and upon lyophilization afforded
white floccular solid 1 (120 mg). Anal. calcd. for C
27H
41N
11O
4 • 2.25 TFA • 1.0 H
2O (858.26): C, 44.08; H, 5.13; N, 17.95; F, 14.94. Found: C, 43.82; H, 5.27; N, 17.91;
F, 14.50. FAB-MS m/e 584.9 (MH
+).
1H NMR (DMSO / D
2O) 7.25 (m, 5H), 4.5 (dd, 1H), 4.4 (dd, 1H), 4.28 (dd, 1H), 3.1 - 2.95 (m, 3H), 2.8
(dd, 1H), 1.8 - 1.35 (m, 11H), 1.3 - 1.0 (m, 4H), 0.9 (m, 2H).
EXAMPLE 2
N- (5-Bromopyridin-3-yl-carbonyl)-cyclohexylalanyl-argininyl-phenylalanine amide (2)
[0054]

Fmoc-phenylalanine amide (3.87 g, 10 mm) was stirred in ACN (100 mL) and DEA ( 5 mL)
was added and stirred at RT for 1 hr. The solution was evaporated
in vacuo to an oil, which was triturated 3X with hexane (100 mL) and dissolved in ACN (100
mL); Fmoc-Arg(PMC)-OH (6.63 g, 10 mm) and HOBT (1.53 g, 10 mm) were added, followed
by DCC (4.1 g, 20 mm) and solution was stirred at RT. The urea by-product was filtered
and the filtrate was evaporated
in vacuo to an oil, which was triturated 3X with hexane (100 mL). The crude product was stirred
in ACN (100 mL) and DEA (5 mL) was added and stirred at RT for 1 hr. The solution
was evaporated
in vacuo to an oil, which was triturated 3X with hexane (100 mL) to a solid. This dipeptide
was combined in ACN (100 mL) with Fmoc-Cha-OH (3.93 g, 10 mm) and HOBT (1.53 g, 10
mm) and then DIC (2.52 g, 20 mm) was added and reaction stirred at RT for 16 hr. Solid
tripeptide was filtered; tripeptide may also be recovered from the filtrate via evaporation
and silica gel column chromatography. The tripeptide (5.0 g, 5 mm) was stirred in
ACN (100 mL) containing DEA (5 mL) until deprotection is complete and then evaporated
in vacuo and triturated with hexane 3X (100 mL). This was combined in ACN (100 mL) and 5-brcmonicotinic
acid (1.01 g, 5 mm) and HOBT (0.76 g, 5 mm) were added in, followed by DIC (1.26 g,
10 mm) and stirred at RT for 16 hr. The solution was evaporated
in vacuo and purified via silica gel column chromatography. This protected product was then
stirred with DCM/TFA (1:1; 50 mL) for 1 hr and then evaporated
in vacuo to an oil, which was triturated 3X with Et
2O (100 mL) to afford white solid 3 as a triflouroacetate salt: MS m/e 657.4/659.4
(MH
+).
1H NMR (DMSO) 9.0 (s, 1H), 8.9 (s, 1H), 8.8 (d, 1H), 8.5 (s, 1H), 8.2 (d, 1H), 7.8
(d, 1H), 7.4 (s, 2H), 7.1 - 7.3 (m, 6H), 4.5 (m, 2H), 4.2 (q, 1H), 4.0 (s, 1H), 3.0
(m, 1H), 2.8 (q, 1H), 1.3 - 1. 8 (m, 12H) , 1.1 (m, 4H), 0.9 (m, 3H).
EXAMPLE 3
[0055] As a specific embodiment of an oral composition, 100 mg of the compound 1 of Example
1 is formulated with sufficient finely divided lactose to provide a total amount of
580 to 590 mg to fill a size O hard gel capsule.
BIOLOGY
[0056] The compounds of the present invention modulate platelet activation induced by thrombin's
proteolytic cleavage of its platelet surface receptor, and thereby activate / inhibit
platelet aggregation. Compounds that exhibit agonist activity may be expected to aid
in wound healing and tissue repair, while antagonist compounds may be useful in treating
platelet-mediated thrombotic disorders such as arterial and venous thrombosis, acute
myocardial infarction, reocclusion following thrombolytic therapy and angioplasty,
and a variety of vaso-occlusive disorders.
EXAMPLE 4
IN VITRO THROMBIN RECEPTOR BINDING ASSAY.
[0057] CHRF membranes (
Jones, Biochim. Biophys. Acta 1992, 1136, 272) are thawed from -70°C, centrifuged at maximum speed for 5 min, washed twice with
binding buffer (50 mM HEPES containing 5 mM MgCl
2 and 0.1% BSA), and resuspended in binding buffer (25 g/100 mL). 100 1 membranes are
added to the 24-Wallac plates and delivered to the Tomtech apparatus. In a typical
experiment, 6 1 of samples (from a 125 g/mL intermediary plate, 20%DMSO) and 44 1
buffer are delivered to the plates (final conc. of compounds is 3.7 g/mL, 0.6% DMSO).
Similarly, 6 1 20%DMSO and 44 1 buffer are delivered to both column 1 (NSB) and column
12 (TB). 10 1 Ser-pFPhe-Har-Leu-Har-Lys-Tyr-NH
2 (721-40; 500 M in deionized water) is added to column 1. 50 1 tritiated 721-40 (specific
activity 46 Ci/mmol) is added to all the wells. The plates are mixed well for 20 seconds,
incubated for 30 min, and then harvested with 10 mM HEPES/138 mM NaCl using the Skatron
harvester. The filters (GF/C Brandel FPXLR 296 filters are presoaked 3 h in 0.5% polyethylenimine
in HEPES/0.1 M N-acetylglucosamine) are set in saran wrap and dried for 3 min in the
microwave, and placed in sample bags (Wallac 1450-432). 4.5 mL scintillation fluid
(Wallac, Betaplate Scint 1205-440) is added. The bags are sealed, placed in filter
cassettes (Wallac 1450-104), and analyzed on the microbeta counter.
EXAMPLE 5
IN VITRO AGONIST PLATELET AGGREGATION ASSAY / INHIBITION OF THROMBIN-INDUCED GEL-FILTERED
PLATELET AGGREGATION ASSAY.
[0058] The percentage of platelet aggregation is calculated as an increase in light transmission
of compound-treated platelet concentrate vs. control-treated platelet concentrate.
Human blood is obtained from drug free, normal donors into tubes containing 0.13 M
sodium citrate. Platelet rich plasma (PRP) is collected by centrifugation of whole
blood at 200 x g for 10 min at 25°C. The PRP (5 mL) is gel filtered through Sepharose
2B (bed volume 50 mL), and the platelet count is adjusted to 2x10
7 platelets per sample. The following constituents are added to a siliconized cuvette:
concentrated platelet filtrate and Tyrode's buffer (0.14 M NaCl, 0.0027 M KCl, 0.012
M NaHCO
3, 0.76 mM Na
2HPO4, 0.0055 M glucose, 2 mg/mL BSA and 5.0 mM HEPES @ pH 7.4) in an amount equal
to 350 1, 50 1 of 20 mM calcium and 50 1 of the test compound. Aggregation is monitored
in a BIODATA aggregometer for the 3 min following the addition of agonist (thrombin
50 1 of 1 unit/mL).
[0059] While the foregoing specification teaches the principles of the present invention,
with examples provided for the purpose of illustration, it will be understood that
the practice of the invention encompasses all of the usual variations, adaptations
and/or modifications as come within the scope of the following claims and their equivalents.
Features of the invention
[0060]
- 1. A compound represented by the general formula (I):

wherein A1 is an alkyl amino acid residue selected from Cha, Leu and Ile, an amino alkyl amino
acid residue selected from Arg and Lys, or an aryl amino acid residue selected from
Phe, substituted Phe, Tyr, or Trp;
A2 is an amino alkyl amino acid residue selected from Lys, Orn, Arg, and homo Arg;
A3 is an aryl amino acid residue selected from Phe, substituted Phe, homo Phe, Tyr,
Trp, phgly, 2-Thala and 3-Thala, an alkyl amino acid residue selected from Cha, Leu
and Ile, an amido alkyl amino acid selected from Asn and Gln, or an amino alkyl amino
acid residue selected from Arg, homo Arg, Orn and Lys;
X is selected from CO, CS, or SO2;
Y is selected from aryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl,
heteroaryl, substituted heteroaryl, heteroarylethylenyl, substituted heteroarylethylenyl,
arylacrylamidoheteroaryl, substituted arylacrylamidoheteroaryl, heteroarylacrylamidoheteroaryl
and substituted heteroarylacrylamidoheteroaryl, provided that Y is not pyrrolidinyl,
phenyl or 2-aminophenyl;
Z is selected from NH2, NH-alkyl, NH-aralkyl, or an amino alkyl amino acid residue selected from Arg-NH2; and
wherein all amino acids are of the L configuration; and pharmaceutically acceptable
salts thereof.
- 2. The compound of feature 1, wherein
A3 is an aryl amino acid residue selected from Phe, substituted Phe, Tyr, Trp, phgly,
2-Thala and 3-Thala, an alkyl amino acid residue selected from Cha, Leu and Ile, an
amido alkyl amino acid selected from Asn and Gln, or an amino alkyl amino acid residue
selected from Arg, homo Arg, Orn and Lys; and
Y is selected from heteroaryl, substituted heteroaryl, arylacrylamidoheteroaryl, and
substituted arylacrylamidoheteroaryl;
and pharmaceutically acceptable salts thereof.
- 3. The compound of feature 2, wherein
A1 is an alkyl amino acid residue selected from Cha, Leu and Ile, or an aryl amino acid
residue selected from Phe, substituted Phe, Tyr, or Trp;
A2 is an amino alkyl amino acid residue selected from Lys or Arg;
A3 is an aryl amino acid residue selected from Phe, substituted Phe, Tyr, Trp, Phgly
and 2-Thala;
X is selected from CO or SO2; and pharmaceutically acceptable salts thereof.
- 4. The compound of feature 3, wherein
X is CO;
Y is selected from benzothiophenyl, substituted benzothiophenyl, pyridinyl, substituted
pyridinyl, triazolyl, substituted triazolyl, chromonyl, quinoxalinyl, thiadiazolyl,
substituted thiadiazolyl, pyrazinyl, substituted pyrazinyl, pyridylethylenyl, substituted
pyridylethylenyl, cinnamamido-triazolyl, substituted cinnamamido-triazolyl, thiophenylacrylamido-triazolyl,
or naphthylacrylamidotriazolyl;
Z is selected from NH2 or Arg-NH2;
and pharmaceutically acceptable salts thereof.
- 5. The compound of feature 4, wherein
A1 is selected from Cha or Phe;
A2 is selected from Arg or Lys;
A3 is selected from Phe;
and pharmaceutically acceptable salts thereof.
- 6. The compound of feature 5, selected from:
(5-Bromopyridin-3-yl)carbonyl-cyclohexylalanyl-arginylphenylalanineamide;
2-Chromonylcarbonyl-cyclohexylalanyl-arginylphenylalanineamide;
(5-Aminotriazol-3-yl)carbonyl-cyclohexylalanyl-arginylphenylalanineamide;
[5-(-Methyl)cinnamamidotriazol-3-yl]carbonylcyclohexylalanyl-arginyl-phenylalanineamide;
{5-[3-(1-Naphthyl)acrylamido]triazol-3-yl}carbonylcyclohexylalanyl-arginyl-phenylalanineamide;
[Quinoxalin-2-yl]carbonyl-cyclohexylalanyl-arginylphenylalanineamide;
[5-(o-Chlorocinnamamido)triazol-3-yl]carbonylcyclohexylalanyl-arginyl-phenylalanineamide;
(6-Aminopyridin-3-yl)carbonyl-cyclohexylalanyl-arginylphenylalanineamide;
(5-Aminotriazol-3-yl)carbonyl-phenylalanyl-arginylphenylalanyl-arginineamide;
(5-Aminotriazol-3-yl)carbonyl-cyclohexylalanyl-lysinylphenylalanineamide;
{5-[3-(2-Thienyl)acrylamido]triazol-3-yl}carbonylcyclohexylalanyl-arginyl-phenylalanineamide;
[5-cinnamamidotriazol-3-yl]carbonyl-cyclohexylalanylarginyl-phenylalanineamide;
(6-Cinnamamidopyridin-3-yl)carbonyl-cyclohexylalanylarginyl-phenylalanineamide; or
(5-Chloro-3-methyl-benzothiophen-2-yl)carbonylcyclohexylalanyl-arginyl-phenylalanineamide;
and pharmaceutically acceptable salts thereof.
- 7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and
a compound of feature 1.
- 8. A pharmaceutical composition made by mixing a compound of feature 1 and a pharmaceutically
acceptable carrier.
- 9. A process for making a pharmaceutical composition comprising mixing a compound
of feature 1 and a pharmaceutically acceptable carrier.
- 10. A method of treating a condition mediated by modulation of the thrombin receptor
in a subject in need thereof comprising administering to the subject a therapeutically
effective amount of the compound of feature 1.
- 11. The method of feature 10, wherein the condition is selected from wound healing,
tissue repair, myocardial infarction, stroke, restenosis, angina, atherosclerosis,
ischemic attacks, inflammation, cancer, osteoporosis, or neurodegenerative disorders.
- 12. The method of feature 11, wherein the therapeutically effective amount of the
compound is about 0.1 to about 300 mg/kg/day.
- 13. The method of feature 12, wherein the therapeutically effective amount of the
compound is about 1 to about 50 mg/kg/day.
- 14. A method of treating a condition modulated by the thrombin receptor in a subject
in need thereof comprising administering to the subject a therapeutically effective
amount of the composition of feature 7.
- 15. The method of feature 14, wherein the condition is selected from wound healing,
tissue repair, myocardial infarction, stroke, restenosis, angina, atherosclerosis,
ischemic attacks, inflammation, cancer, osteoporosis, or neurodegenerative disorders.
- 16. The method of feature 14, wherein the therapeutically effective amount of the
compound is about 0.1 to about 300 mg/kg/day.
- 17. The method of feature 16, wherein the therapeutically effective amount of the
compound is about 1 to about 50 mg/kg/day.